Diverse Fibrosis Architecture and Premature Stimulation Facilitate Initiation of Reentrant Activity Following Chronic Atrial Fibrillation

Angel, Nathan; Li, Li; MacLeod, Robert S.; Marrouche, Nassir F.; Ranjan, Ravi; Dosdall, Derek J.

doi:10.1111/jce.12773

Cited by 28 publications

(25 citation statements)

References 34 publications

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“…In case of interstitial fibrosis, AF-induced increase in tissue anisotropy (Kawara et al, 2001; Koura et al, 2002; Verheule et al, 2013; Angel et al, 2015; Krul et al, 2015) resulted in multiple conduction blocks and wave breakdown throughout the 3D atria (Figure 7C). This was the only condition where the 3D atria model produced a sustained AF-like patterns with multiple re-entrant wavelets.…”

Section: Discussionmentioning

confidence: 99%

Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

et al. 2016

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Introduction: The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors) sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers.Methods: 3D atrial models integrated human atrial geometry, rule-based fiber orientation, region-specific electrophysiology, and AF-induced ionic remodeling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F) coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0–healthy tissue, 5–dense fibrosis) were identified based on LGE MRI intensity and modeled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2) fibrosis was considered for comparison.Results: In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV). In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors stabilized in fibrotic regions. The rotors propagated slowly around the border zones of patchy fibrosis (levels 3–4), failing to spread into inner areas of dense fibrosis.Conclusion: Rotors stabilize in the border zones of patchy fibrosis in 3D atria, where slow conduction enable the development of circuits within relatively small regions. Our results can provide a mechanistic explanation for the clinical efficacy of ablation around fibrotic regions.

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Section: Discussionmentioning

confidence: 99%

Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

et al. 2016

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“…Finally, the degree, type and pattern of fibrosis varies considerably for different kinds of diseases or during different stages of one particular pathology [44]. Therefore, we have investigated how the percentage of fibrosis, ϕ , and the size of a fibrotic region influence the probability to generate microreentries and create ectopic pacemakers in cardiac tissue.…”

Section: Introductionmentioning

confidence: 99%

Reentry and Ectopic Pacemakers Emerge in a Three-Dimensional Model for a Slab of Cardiac Tissue with Diffuse Microfibrosis near the Percolation Threshold

Alonso¹,

Santos²,

Bär³

2016

PLoS ONE

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Arrhythmias in cardiac tissue are generally associated with irregular electrical wave propagation in the heart. Cardiac tissue is formed by a discrete cell network, which is often heterogeneous. Recently, it was shown in simulations of two-dimensional (2D) discrete models of cardiac tissue that a wave crossing a fibrotic, heterogeneous region may produce reentry and transient or persistent ectopic activity provided the fraction of conducting connections is just above the percolation threshold. Here, we investigate the occurrence of these phenomena in three-dimensions by simulations of a discrete model representing a thin slab of cardiac tissue. This is motivated (i) by the necessity to study the relevance and properties of the percolation-related mechanism for the emergence of microreentries in three dimensions and (ii) by the fact that atrial tissue is quite thin in comparison with ventricular tissue. Here, we simplify the model by neglecting details of tissue anatomy, e. g. geometries of atria or ventricles and the anisotropy in the conductivity. Hence, our modeling study is confined to the investigation of the effect of the tissue thickness as well as to the comparison of the dynamics of electrical excitation in a 2D layer with the one in a 3D slab. Our results indicate a strong and non-trivial effect of the thickness even for thin tissue slabs on the probability of microreentries and ectopic beat generation. The strong correlation of the occurrence of microreentry with the percolation threshold reported earlier in 2D layers persists in 3D slabs. Finally, a qualitative agreement of 3D simulated electrograms in the fibrotic region with the experimentally observed complex fractional atrial electrograms (CFAE) as well as strong difference between simulated electrograms in 2D and 3D were found for the cases where reentry and ectopic activity were triggered by the micro-fibrotic region.

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“…[37] In a persistent AF goat model, this pattern has been shown to increase electrical anisotropy. [38] Furthermore, optical mapping of human left atrial appendages in patients with AF have corroborates the findings of slower conduction, and structural and functional block, which are arrhythmogenic. [39,40] …”

Section: Extracellular Changesmentioning

confidence: 58%

“…[45] The presence of these abnormal cell types is associated with abnormal conduction. [38,[46][47][48] …”

Section: Cellular Changesmentioning

confidence: 99%

Assessment of atrial fibrosis for the rhythm control of atrial fibrillation

Begg

Holden

Lip

et al. 2016

International Journal of Cardiology

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Rhythm control of atrial fibrillation (AF) remains challenging, with modest long term success rates. Atrial fibrosis has been associated with AF, but the clinical utility of assessment of this fibrosis has yet to be fully elucidated. In this paper we review the current state of understanding of the pathophysiology of atrial fibrosis in AF, and its impact upon the instigation and propagation of the arrhythmia. Fibrosis causes an increase in volume of dysfunctional extracellular matrix, and is associated with cellular alterations such as hypertrophy, apoptosis and membrane dysfunction within the atrial myocardium. In turn, these cause pathological alterations to atrial conduction, such as increased anisotropy, conduction block and re-entry, which can lead to AF. We review current methods of assessing atrial fibrosis and their impact upon the prediction of success of interventional rhythm control strategies such as ablation and cardioversion. We focus particularly on circulating biomarkers of fibrosis and scar formation; their role in the fibrotic process, and their value in the prediction of rhythm control success. We also review imaging and invasive electrocardiographic mapping techniques that may identify fibrosis, and again assess their potential predictive value. In this area there exist many unanswered questions, but further work will help to refine techniques to reliably identify and treat those patients who are most likely to benefit from rhythm control treatment strategies.3

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Diverse Fibrosis Architecture and Premature Stimulation Facilitate Initiation of Reentrant Activity Following Chronic Atrial Fibrillation

Cited by 28 publications

References 34 publications

Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

Reentry and Ectopic Pacemakers Emerge in a Three-Dimensional Model for a Slab of Cardiac Tissue with Diffuse Microfibrosis near the Percolation Threshold

Assessment of atrial fibrosis for the rhythm control of atrial fibrillation

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